bims-flamet 2024-11-17 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–11–17
24 papers selected by
Peio Azcoaga, Biodonostia HRI

Mitochondrial regulation in the tumor microenvironment: targeting mitochondria for immunotherapy.
Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression.
Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.
Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.
AXL/GAS6 signaling governs differentiation of tumor-associated macrophages in breast cancer.
Myeloid-Derived Suppressor Cells in Bladder Cancer: An Emerging Target.
Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment.
LncRNAs in tumor metabolic reprogramming and tumor microenvironment remodeling.
Understanding the interplay between extracellular matrix topology and tumor-immune interactions: Challenges and opportunities.
The Dual Role of B Cells in the Tumor Microenvironment: Implications for Cancer Immunology and Therapy.
The mechanism of cytokine regulation of cancer occurrence and development in the tumor microenvironment and its application in cancer treatment: a narrative review.
Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.
Phospholipase D2 downregulates interleukin-1β secretion from tumor-associated macrophages to suppress bladder cancer progression.
Oncolytic virus and CAR-T cell therapy in solid tumors.
Myeloid-derived suppressor cells: Identification and function.
A Comprehensive Exploration of Agents Targeting Tumor Microenvironment: Challenges and Future Perspectives.
C1QTNF Related protein 8 (CTRP8) is a marker of myeloid derived innate immune cell populations in the human breast cancer microenvironment.
Pancreatic Adenocarcinoma Up-Regulated Factor (PAUF) Transforms Human Monocytes into Alternative M2 Macrophages with Immunosuppressive Action.
Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment.
Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer.
Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.
Understanding and measuring mechanical signals in the tumor stroma.
Bimetallic peroxide-based nanotherapeutics for immunometabolic intervention and induction of immunogenic cell death to augment cancer immunotherapy.
Deciphering the Tumor Microenvironment in Prostate Cancer: A Focus on the Stromal Component.

Front Immunol. 2024 ;15 1453886

Mitochondrial regulation in the tumor microenvironment: targeting mitochondria for immunotherapy.

Minseo Ahn, Akhtar Ali, Jae Ho Seo.

  Mitochondrial regulation plays a crucial role in cancer immunity in the tumor microenvironment (TME). Infiltrating immune cells, including T cells, natural killer (NK) cells, and macrophages, undergo mitochondrial metabolic reprogramming to survive the harsh conditions of the TME and enhance their antitumor activity. On the other hand, immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), mast cells, and tumor-associated macrophages (TAMs) rely on mitochondrial regulation to maintain their function as well. Additionally, mitochondrial regulation of cancer cells facilitates immune evasion and even hijacks mitochondria from immune cells to enhance their function. Recent studies suggest that targeting mitochondria can synergistically reduce cancer progression, especially when combined with traditional cancer therapies and immune checkpoint inhibitors. Many mitochondrial-targeting drugs are currently in clinical trials and have the potential to enhance the efficacy of immunotherapy. This mini review highlights the critical role of mitochondrial regulation in cancer immunity and provides lists of mitochondrial targeting drugs that have potential to enhance the efficacy of cancer immunotherapy.

Keywords:  TME; immune evasion; immunotherapy; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2024.1453886
Int J Mol Sci. 2024 Oct 28. pii: 11558. [Epub ahead of print]25(21):

Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression.

Rasha S Abo El Alaa, Wafaa Al-Mannai, Nour Darwish, Layla Al-Mansoori.

  Adipose-derived stromal cells (ASCs) and cancer-associated fibroblasts (CAFs) play pivotal roles in the tumor microenvironment (TME), significantly influencing cancer progression and metastasis. This review explores the plasticity of ASCs, which can transdifferentiate into CAFs under the influence of tumor-derived signals, thus enhancing their secretion of extracellular matrix components and pro-inflammatory cytokines that promote tumorigenesis. We discuss the critical process of the epithelial-to-mesenchymal transition (EMT) facilitated by ASCs and CAFs, highlighting its implications for increased invasiveness and therapeutic resistance in cancer cells. Key signaling pathways, including the transforming growth factor-β (TGF-β), Wnt/β-catenin, and Notch, are examined for their roles in regulating EMT and CAF activation. Furthermore, we address the impact of epigenetic modifications on ASC and CAF functionality, emphasizing recent advances in targeting these modifications to inhibit their pro-tumorigenic effects. This review also considers the metabolic reprogramming of ASCs and CAFs, which supports their tumor-promoting activities through enhanced glycolytic activity and lactate production. Finally, we outline potential therapeutic strategies aimed at disrupting the interactions between ASCs, CAFs, and tumor cells, including targeted inhibitors of key signaling pathways and innovative immunotherapy approaches. By understanding the complex roles of ASCs and CAFs within the TME, this review aims to identify new therapeutic opportunities that could improve patient outcomes in cancer treatment.

Keywords:  EMT; adipose tissue; cancer; fibroblasts; stromal cells

DOI:  https://doi.org/10.3390/ijms252111558
Front Immunol. 2024 ;15 1461455

Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.

Oliver Goldmann, Eva Medina.

  Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions.

Keywords:  immunosuppression; infection; metabolic reprogramming; metabolism; myeloid-derived suppressor cells; tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1461455
Cancer Immunol Res. 2024 Nov 12.

Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.

Shunli Dong, Cong Ye, Bin Li, Fanglin Lv, Lu Zhang, Shumin Yang, Fang Wang, Mingxian Zhu, Mingxuan Zhou, Fanfan Guo, Zhenyun Li, Lei Peng, Cheng Ji, Xialiang Lu, Yan Cheng, Xingcong Ren, Youguo Chen, Jinhua Zhou, Jinming Yang, Yi Zhang.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade (ICB) therapy. Here, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of EOC, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME), led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16, by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small molecule inhibitor of NAC1, was able to sensitize mice-bearing NAC1-expressing ovarian tumors to anti-PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of ICB therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0084
Exp Cell Res. 2024 Nov 05. pii: S0014-4827(24)00415-4. [Epub ahead of print] 114324

AXL/GAS6 signaling governs differentiation of tumor-associated macrophages in breast cancer.

Suman Purohit, Gunjan Mandal, Subir Biswas, Shauryabrota Dalui, Arnab Gupta, Sougata Roy Chowdhury, Arindam Bhattacharyya.

  Most epithelial cancers are infiltrated by prognostically relevant myelomonocytic cells. Immunosuppressive tumor associated macrophages (TAMs) and their precursor monocytic-MDSCs have previously been associated with worse outcomes in human breast cancer (BCa), yet the mechanism of immunosuppressive TAMs-polarization from myelomonocytic precursors is not completely understood. In this study, we show that persuaded AXL/GAS6 pathway alters macrophage phenotype from HLA-DRhighCD206low CD163low classical phagocytic into HLA-DRlowCD206highCD163high immunosuppressive ones with accelerated BCa progression, and increased angiogenesis signature and invasion ability of cancer cells at tumor beds. Notably, both AXL and GAS6 expressions are upregulated in human invasive breast carcinoma, with maximum expression in triple negative histology type. Mechanistically, we demonstrate that AXL/GAS6 signaling drives immunosuppression by governing increased immunosuppressive IL10 production while dampening IL-1β expression within the tumor microenvironment (TME) of BCa. Further, AXL/GAS6 signaling promotes angiogenesis through the activation of PI3K/AKT and NF-κB signaling pathways. Our results unveil role of AXL/GAS6 axis in the differentiation of TAMs, which governs malignant growth, and suggest that therapies that uncouple AXL/GAS6 axis may exhibit therapeutic opportunity for otherwise undruggable Triple Negative Breast Cancer (TNBC) patients.

Keywords:  AXL; GAS6; M1 macrophage; M1/M2 ratio; M2 macrophage; angiogenesis; immunosuppression; inflammation

DOI:  https://doi.org/10.1016/j.yexcr.2024.114324
Cells. 2024 Oct 27. pii: 1779. [Epub ahead of print]13(21):

Myeloid-Derived Suppressor Cells in Bladder Cancer: An Emerging Target.

Clément Klein, Samy Mebroukine, Mathilde Madéry, Alexandra Moisand, Thomas Boyer, Nicolas Larmonier, Grégoire Robert, Charlotte Domblides.

  Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette-Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies.

Keywords:  biomarker; bladder cancer; immune inhibition; immunotherapy; myeloid-derived suppressor cells; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13211779
Int J Mol Sci. 2024 Oct 31. pii: 11735. [Epub ahead of print]25(21):

Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment.

Tasuku Matsuoka, Masakazu Yashiro.

  Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of tumor cells, and interactions between the cellular and molecular components of the TME-e.g., inflammatory cells, fibroblasts, vasculature cells, and innate and adaptive immune cells-promote the aggressiveness of cancer cells and dissemination to distant organs. This review summarizes the roles of various TME cells and molecules in regulating the malignant progression and metastasis of GC. We also address the important roles of signaling pathways in mediating the interaction between cancer cells and the different components of the GC TME. Finally, we discuss the implications of these molecular mechanisms for developing novel and effective therapies targeting molecular and cellular components of the GC TME to control the malignant progression of GC.

Keywords:  gastric cancer; immune tolerance; microbiota; signaling pathway; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252111735
Front Immunol. 2024 ;15 1467151

LncRNAs in tumor metabolic reprogramming and tumor microenvironment remodeling.

Jianhang Jiao, Yangzhi Zhao, Qimei Li, Shunzi Jin, Zhongshan Liu.

  The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of tumor cells, immune cells, supporting cells, and the extracellular matrix. Typically, the TME is characterized by an immunosuppressive state. To meet the demands of rapid proliferation, cancer cells undergo metabolic reprogramming, which enhances their biosynthesis and bioenergy supply. Immune cells require similar nutrients for activation and proliferation, leading to competition and immunosuppression within the TME. Additionally, tumor metabolites inhibit immune cell activation and function. Consequently, an immunosuppressed and immune-tolerant TME promotes cancer cell proliferation and metastasis. Long non-coding RNAs (lncRNAs), a category of non-coding RNA longer than 200 nucleotides, regulate tumor metabolic reprogramming by interacting with key enzymes, transporters, and related signaling pathways involved in tumor metabolism. Furthermore, lncRNAs can interact with both cellular and non-cellular components in the TME, thereby facilitating tumor growth, metastasis, drug resistance, and inducing immunosuppression. Recent studies have demonstrated that lncRNAs play a crucial role in reshaping the TME by regulating tumor metabolic reprogramming. In this discussion, we explore the potential mechanisms through which lncRNAs regulate tumor metabolic reprogramming to remodel the TME. Additionally, we examine the prospects of lncRNAs as targets for anti-tumor therapy and as biomarkers for tumor prognosis.

Keywords:  lncRNAs; metabolic reprogramming; tumor immunity; tumor immunotherapy; tumor microenvironment remodeling

DOI:  https://doi.org/10.3389/fimmu.2024.1467151
Oncotarget. 2024 Nov 07. 15 768-781

Understanding the interplay between extracellular matrix topology and tumor-immune interactions: Challenges and opportunities.

Yijia Fan, Alvis Chiu, Feng Zhao, Jason T George.

  Modern cancer management comprises a variety of treatment strategies. Immunotherapy, while successful at treating many cancer subtypes, is often hindered by tumor immune evasion and T cell exhaustion as a result of an immunosuppressive tumor microenvironment (TME). In solid malignancies, the extracellular matrix (ECM) embedded within the TME plays a central role in T cell recognition and cancer growth by providing structural support and regulating cell behavior. Relative to healthy tissues, tumor associated ECM signatures include increased fiber density and alignment. These and other differentiating features contributed to variation in clinically observed tumor-specific ECM configurations, collectively referred to as Tumor-Associated Collagen Signatures (TACS) 1-3. TACS is associated with disease progression and immune evasion. This review explores our current understanding of how ECM geometry influences the behaviors of both immune cells and tumor cells, which in turn impacts treatment efficacy and cancer evolutionary progression. We discuss the effects of ECM remodeling on cancer cells and T cell behavior and review recent in silico models of cancer-immune interactions.

Keywords:  ECM; tumor microenvironment; tumor-T cell evolution

DOI:  https://doi.org/10.18632/oncotarget.28666
Int J Mol Sci. 2024 Nov 04. pii: 11825. [Epub ahead of print]25(21):

The Dual Role of B Cells in the Tumor Microenvironment: Implications for Cancer Immunology and Therapy.

Hao Yang, Zhiru Zhang, Jijun Li, Kun Wang, Wanting Zhu, Yingyue Zeng.

  The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for anti-tumor therapies. The dual nature of B cells, exhibiting both tumor-suppressive and tumor-promoting functions, has garnered significant attention. Understanding the distinct effects of various B cell subsets on different tumors could pave the way for novel targeted tumor therapies. This review provides a comprehensive overview of the heterogeneous B cell subsets and their multifaceted roles in tumorigenesis, as well as the therapeutic potential of targeting B cells in cancer treatment. To develop more effective cancer immunotherapies, it is essential to decipher the heterogeneity of B cells and their roles in shaping the TME.

Keywords:  B cell; B cell heterogeneity; anti-tumor therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252111825
Transl Cancer Res. 2024 Oct 31. 13(10): 5649-5663

The mechanism of cytokine regulation of cancer occurrence and development in the tumor microenvironment and its application in cancer treatment: a narrative review.

Run Qu, Yanhong Zhao, Yuzhe Zhang.

   Background and Objective: The occurrence and development of tumors in human tissues widely depend on their surrounding environment, known as the tumor microenvironment (TME), which comprises various cells, molecules, and blood vessels. Through modifications, organization, and integration, these elements serve as potential therapeutic targets in anti-cancer therapy, supporting and promoting the proliferation, invasion, and metabolism of tumor cells. Cytokines within TME are responsible for immune cell activation, proliferation, and differentiation, thereby influencing the tumor's behavior. This article reviews the use of cytokines in tumor immunotherapy and combs the network signals that cytokines mediate in the development of malignancies.
Methods: A literature search of international sources was carried out on the PubMed and Web of Science databases, using main keywords such as "tumor immunotherapy", "cytokines", "chemokines", "tumor microenvironment", "recombinant cytokine engineering", and "tumor necrosis factor superfamily".
Key Content and Findings: The review provides a thorough summary of the functions of tumor necrosis factor superfamilies, chemokines, and interleukins within the TME as well as their therapeutic uses. Their potential as novel targets for tumor treatment is also evaluated. Furthermore, this paper focuses on various feasible strategies for recombinant cytokines reported in recent years, especially the cytokine engineering methods for targeting tumors. Ultimately, this paper contributes to an enhanced understanding among researchers of the mechanisms underlying the impact of the TME on disease development, thereby laying a solid foundation for the future development of new tumor therapies based on cytokines within the TME.
Conclusions: Cytokine immunotherapy holds promise on antitumor therapy. It is anticipated that the effectiveness of tumor treatment and the quality of life for tumor patients will continue to improve with ongoing research and development in this field.

Keywords:  Cytokines; tumor immunotherapy; tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/tcr-24-679
Cancer Res. 2024 Nov 15.

Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.

Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech.

Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-4027
Cancer Sci. 2024 Nov 11.

Phospholipase D2 downregulates interleukin-1β secretion from tumor-associated macrophages to suppress bladder cancer progression.

Kazuki Hamada, Yoshiyuki Nagumo, Shuya Kandori, Bunpei Isoda, Shuhei Suzuki, Keisuke Sano, Shotaro Sakka, Kozaburo Tanuma, Satoshi Nitta, Masanobu Shiga, Hiromitsu Negoro, Bryan J Mathis, Yuji Funakoshi, Hiroyuki Nishiyama.

  The tumor microenvironment (TME) modulates therapeutic response and prognosis in patients with bladder cancer (BC). The roles of two phospholipase D (PLD) isoforms, PLD1 and PLD2 (hydrolysis of phosphatidylcholine to phosphatidic acid), in cancer cells have been well-studied in numerous cancer types, but their roles in the TME remain unclear. We used a mouse BC Pld2-KO carcinogenesis model and global transcriptomic analysis to reveal that PLD2 was significantly involved in BC progression through immunosuppressive pathways in the TME. We therefore focused on PLD2 and tumor-associated macrophages (TAMs), which were increased in Pld2-KO mice and further associated with poor prognoses in BC patients. In vitro, we found that Pld2-KO mouse TAMs had significantly enhanced proliferation, correlating closely with increased interleukin-1β (IL-1β) production. These results indicate that PLD2 suppresses BC progression by regulation of IL-1β secretion from TAMs in the TME, suggesting that PLD2 could serve as a potential therapeutic target for modifying the TME in BC.

Keywords:  IL‐1β; bladder cancer; phospholipase D2; tumor microenvironment; tumor‐associated macrophage

DOI:  https://doi.org/10.1111/cas.16393
Front Immunol. 2024 ;15 1455163

Oncolytic virus and CAR-T cell therapy in solid tumors.

Eleonora Ponterio, Tobias Longin Haas, Ruggero De Maria.

  Adoptive immunotherapy with T cells, genetically modified to express a tumor-reactive chimeric antigen receptor (CAR), is an innovative and rapidly developing life-saving treatment for cancer patients without other therapeutic opportunities. CAR-T cell therapy has proven effective only in hematological malignancies. However, although by now only a few clinical trials had promising outcomes, we predict that CAR-T therapy will eventually become an established treatment for several solid tumors. Oncolytic viruses (OVs) can selectively replicate in and kill cancer cells without harming healthy cells. They can stimulate an immune response against the tumor, because OVs potentially stimulate adaptive immunity and innate components of the host immune system. Using CAR-T cells along with oncolytic viruses may enhance the efficacy of CAR-T cell therapy in destroying solid tumors by increasing the tumor penetrance of T cells and reducing the immune suppression by the tumor microenvironment. This review describes recent advances in the design of oncolytic viruses and CAR-T cells while providing an overview of the potential combination of oncolytic virotherapy with CAR-T cells for solid cancers. In this review, we will focus on the host-virus interaction in the tumor microenvironment to reverse local immunosuppression and to develop CAR-T cell effector function.

Keywords:  CAR T cells; cancer; immunotherapy; oncolytic viruses; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1455163
Methods Cell Biol. 2024 ;pii: S0091-679X(24)00181-X. [Epub ahead of print]190 151-169

Myeloid-derived suppressor cells: Identification and function.

Paola Vacca, Maria Teresa Bilotta, Lorenzo Moretta, Nicola Tumino.

  Myeloid-derived suppressor cells (MDSCs) are cells that play a regulatory role in immune responses and inflammation. They can have both positive and negative effects on various diseases, including cancer, infections, sepsis, and trauma. MDSCs inhibit immune cells by releasing immunosuppressive factors and can be categorized as monocytic (M) or polymorphonuclear (PMN) cell lineages. Most MDSCs are PMN-MDSC and are found in the peripheral blood (PB) and in the tissue microenvironment of tumor and inflamed patients, where they can directly inhibit immune cell activity and promote tumor progression. Various markers have been suggested for their identification, but in order to be defined as MDSC, their inhibitory capacity has to be certified. In this article, we summarize the identification and functional protocol for characterizing MDSCs, focusing on PMN-MDSC.

Keywords:  Immunomodulatory cells; Myeloid-derived suppressor cells; Tumor microenviornment

DOI:  https://doi.org/10.1016/bs.mcb.2024.07.009
J Immunother Precis Oncol. 2024 Nov;7(4): 283-299

A Comprehensive Exploration of Agents Targeting Tumor Microenvironment: Challenges and Future Perspectives.

Carlos Diego Holanda Lopes, Camila Braganca Xavier, Carlos Torrado, Ana Carolina Veneziani, Thais Baccili Cury Megid.

  The tumor microenvironment (TME) encompasses the complex and diverse surroundings in which tumors arise. Emerging insights highlight the TME's critical role in tumor development, progression, metastasis, and treatment response. Consequently, the TME has attracted significant research and clinical interest, leading to the identification of numerous novel therapeutic targets. Advances in molecular technologies now enable detailed genomic and transcriptional analysis of cancer cells and the TME and the integration of microenvironmental data to the tumor genomic landscape. This comprehensive review discusses current progress in targeting the TME for drug development, addressing associated challenges, strategies for modulating the pro-tumor microenvironment, and the discovery of new targets.

Keywords:  challenges; mechanisms; resistance; targets; tumor microenvironment

DOI:  https://doi.org/10.36401/JIPO-24-23
Biochem Pharmacol. 2024 Nov 12. pii: S0006-2952(24)00624-5. [Epub ahead of print] 116624

C1QTNF Related protein 8 (CTRP8) is a marker of myeloid derived innate immune cell populations in the human breast cancer microenvironment.

Leanne Arreza, Thatchawan Thanasupawat, Sai Nivedita Krishnan, Matthew Kraljevic, Thomas Klonisch, Sabine Hombach-Klonisch.

  Innate immune cells in the tumor microenvironment (TME) play an important role in breast cancer (BC) metastatic spread and influence patient survival. Macrophages differentiate along a proinflammatory M1 to protumorigenic M2 phenotype spectrum which affects distinct functions, like angiogenesis and cytokine production, and modulates BC aggressiveness and affects patient survival. Mast cells (MCs) are myeloid derived cells that serve as the first line of innate immune defense but their role in the TME of BC is not well understood. In this study, we have identified a subpopulation of innate immune cells that shows strong immunopositivity for the least studied adipokine CTRP8. Using a new and highly specific polyclonal antiserum on patient BC tissues, we identify a subset of tryptase + MCs and CD68 + macrophages co-expressing immunoreactive CTRP8. In M1 polarized THP-1 myeloid cells, this adipokine stimulated increased secretion of pro-inflammatory cytokines and elevated expression of the relaxin/ CTRP8 receptor RXFP1. Comparative analysis of secreted cytokine profiles in THP-1 M1 macrophages exposed to either CTRP8, relaxin-2 (RLN2), or the small molecule RXFP1 agonist ML-290 revealed ligand-specific cytokine signatures. Our study identified novel subsets of CTRP8 + myeloid derived innate immune cells and links this adipokine to pro-inflammatory events in the TME of BC.

Keywords:  CD68; CTRP8; Cytokines; Mast cells; Myeloid cells; THP1; Tryptase

DOI:  https://doi.org/10.1016/j.bcp.2024.116624
Int J Mol Sci. 2024 Oct 27. pii: 11545. [Epub ahead of print]25(21):

Pancreatic Adenocarcinoma Up-Regulated Factor (PAUF) Transforms Human Monocytes into Alternative M2 Macrophages with Immunosuppressive Action.

Yeon Jeong Kim, Sitansu Sekhar Nanda, Fen Jiang, Seung Yeon Pyo, Jin-Yeong Han, Sang Seok Koh, Tae Heung Kang.

  Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) promote immune evasion, cancer cell proliferation, and metastasis. Ongoing research is focused on finding ways to prevent tumor growth by inhibiting TAM polarization, which has shown a correlation with unfavorable prognosis in clinical studies. Pancreatic adenocarcinoma up-regulated factor (PAUF) is a protein secreted from pancreatic cancer (PC) and acts as a TME modulator that affects the TME by acting on not only cancer cells but also stromal cells and immune cells. Tumor cells can evade the immune system by PAUF binding to Toll-like receptor (TLR) in monocytes, as this research shows. In this study, the examination centered around the recruitment of human monocytes by PAUF and the subsequent differentiation into macrophages. In an in vitro chemotaxis assay, PAUF induced chemotactic migration of TLR2-mediated monocytes. In addition, PAUF induced differentiation of monocytes into M2 macrophages, which was verified based on expressing surface markers and cytokines and morphological analysis. The inhibition of T cell proliferation and function was observed in differentiated M2 macrophages. To conclude, these findings indicate that PAUF functions as a promoter of cancer progression by regulating the recruitment and differentiation of macrophages within TMEs, ultimately causing immunosuppression.

Keywords:  M2 macrophages; PAUF; TAM; TLR; TME

DOI:  https://doi.org/10.3390/ijms252111545
Adv Sci (Weinh). 2024 Nov 07. e2403423

Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment.

Xiaoye Shi, Xiangshu Cheng, Aimin Jiang, Wenjie Shi, Lingxuan Zhu, Weiming Mou, Antonino Glaviano, Zaoqu Liu, Quan Cheng, Anqi Lin, Linhui Wang, Peng Luo.

  B cells are crucial component of humoral immunity, and their role in the tumor immune microenvironment (TME) has garnered significant attention in recent years. These cells hold great potential and application prospects in the field of tumor immunotherapy. Research has demonstrated that the TME can remodel various B cell functions, including proliferation, differentiation, antigen presentation, and antibody production, thereby invalidating the anti-tumor effects of B cells. Concurrently, numerous immune checkpoints (ICs) on the surface of B cells are upregulated. Aberrant B-cell IC signals not only impair the function of B cells themselves, but also modulate the tumor-killing effects of other immune cells, ultimately fostering an immunosuppressive TME and facilitating tumor immune escape. Blocking ICs on B cells is beneficial for reversing the immunosuppressive TME and restoring anti-tumor immune responses. In this paper, the intricate connection between B-cell ICs and the TME is delved into, emphasizing the critical role of targeting B-cell ICs in anti-tumor immunity, which may provide valuable insights for the future development of tumor immunotherapy based on B cells.

Keywords:  B cell; antitumor immunity; immune checkpoint (IC); immune checkpoint inhibitor (ICI); tumor immune microenvironment (TME)

DOI:  https://doi.org/10.1002/advs.202403423
Cancer Res. 2024 Nov 12.

Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer.

Wenfeng Zeng, Ruihua Zhang, Penghan Huang, Minxia Chen, Houying Chen, Xin Zeng, Jiang Liu, Jiahui Zhang, Di Huang, Liyan Lao.

Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment (TME) need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MBOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL-1beta+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MBOAT1 expression via IL-1beta/IL-1R1/NF-kappaB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL-8 and S100A9 to replenish the neutrophil pool in the TME. Ferroptotic neutrophils in turn fostered Fer-CD4 T cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL-1beta+ CD4+ T cells or IL-1R1+ neutrophils broke the crosstalk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1941
World J Gastroenterol. 2024 Nov 07. 30(41): 4490-4495

Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.

Wei-Lu Wang, Paul Kwong Hang Tam, Yan Chen.

  In this article, we comment on the article by Huang et al. The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al's study that require further research, providing guidance and new directions for similar studies.

Keywords:  Hepatocarcinoma cell; Liver cancer; M2 tumor-associated macrophages; Polarization; Wingless/integrated signaling pathway

DOI:  https://doi.org/10.3748/wjg.v30.i41.4490
FEBS Open Bio. 2024 Nov 10.

Understanding and measuring mechanical signals in the tumor stroma.

Fàtima de la Jara Ortiz, Chiara Cimmino, Maurizio Ventre, Alessandra Cambi.

  The tumor microenvironment (TME) is well known for its immune suppressive role, especially in solid tumors which are characterized by a thick, dense stroma. Apart from cell-cell interactions and biochemical signals, the tumor stroma is also characterized by its distinct mechanical properties, which are dictated by the composition and architecture of its extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs) are the main producers and remodelers of the stromal ECM, and their heterogeneity has recently become a focus of intense research. This review describes recent findings highlighting CAF subtypes and their specific functions, as well as the development of 3D models to study tumor stroma mechanics in vitro. Finally, we discuss the quantitative techniques used to measure tissue mechanical properties at different scales. Given the diagnostic and prognostic value of stroma stiffness and composition, and the recent development of anti-tumor therapeutic strategies targeting the stroma, understanding and measuring tumor stroma mechanical properties has never been more timely or relevant.

Keywords:  cancer‐associated fibroblast; extracellular matrix; mechanobiology; stiffness; tumor mechanics

DOI:  https://doi.org/10.1002/2211-5463.13923
Biomaterials. 2024 Oct 30. pii: S0142-9612(24)00469-1. [Epub ahead of print]315 122934

Bimetallic peroxide-based nanotherapeutics for immunometabolic intervention and induction of immunogenic cell death to augment cancer immunotherapy.

Min Han, Shiying Zhou, Zunde Liao, Chen Zishan, Xiangting Yi, Chuanbin Wu, Dongmei Zhang, Yao He, Kam W Leong, Yiling Zhong.

  Immunotherapy has transformed cancer treatment, but its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME), which are predominantly influenced by the metabolism of cancer cells. Among these metabolic pathways, the indoleamine 2,3-dioxygenase (IDO) pathway is particularly crucial, as it significantly contributes to TME suppression and influences immune cell activity. Additionally, inducing immunogenic cell death (ICD) in tumor cells can reverse the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy. Herein, we develop CGDMRR, a novel bimetallic peroxide-based nanodrug based on copper-cerium peroxide nanoparticles. These nanotherapeutics are engineered to mitigate tumor hypoxia and deliver therapeutics such as 1-methyltryptophan (1MT), glucose oxidase (GOx), and doxorubicin (Dox) in a targeted manner. The design aims to alleviate tumor hypoxia, reduce the immunosuppressive effects of the IDO pathway, and promote ICD. CGDMRR effectively inhibits the growth of 4T1 tumors and elicits antitumor immune responses by leveraging immunometabolic interventions and therapies that induce ICD. Furthermore, when CGDMRR is combined with a clinically certified anti-PD-L1 antibody, its efficacy in inhibiting tumor growth is enhanced. This improved efficacy extends beyond unilateral tumor models, also affecting bilateral tumors and lung metastases, due to the activation of systemic antitumor immunity. This study underscores CGDMRR's potential to augment the efficacy of PD-L1 blockade in breast cancer immunotherapy.

Keywords:  Cancer immunotherapy; Immunogenic cell death; Immunometabolic intervention; Nanocarriers; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122934
Cancers (Basel). 2024 Oct 31. pii: 3685. [Epub ahead of print]16(21):

Deciphering the Tumor Microenvironment in Prostate Cancer: A Focus on the Stromal Component.

Hubert Pakula, Filippo Pederzoli, Giuseppe Nicolò Fanelli, Pier Vitale Nuzzo, Silvia Rodrigues, Massimo Loda.

  Prostate cancer progression is significantly affected by its tumor microenvironment, in which mesenchymal cells play a crucial role. Stromal cells are modified by cancer mutations, response to androgens, and lineage plasticity, and in turn, engage with epithelial tumor cells via a complex array of signaling pathways and ligand-receptor interactions, ultimately affecting tumor growth, immune interaction, and response to therapy. The metabolic rewiring and interplay in the microenvironment play an additional role in affecting the growth and progression of prostate cancer. Finally, therapeutic strategies and novel clinical trials with agents that target the stromal microenvironment or disrupt the interaction between cellular compartments are described. This review underscores cancer-associated fibroblasts as essential contributors to prostate cancer biology, emphasizing their potential as prognostic indicators and therapeutic targets.

Keywords:  cancer-associated fibroblasts (CAFs); castration-resistant prostate cancer (CRPC); mesenchymal cells; prostate cancer (PCa); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers16213685